Multi-site transcutaneous electrical stimulation of the spinal cord for facilitation of locomotion

ABSTRACT

In various embodiments, non-invasive methods to induce motor control in a mammal subject to spinal cord or other neurological injuries are provided. In some embodiments the methods involve administering transcutaneous electrical spinal cord stimulation (tSCS) to the mammal at a frequency and intensity that induces locomotor activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of and priority to U.S. Ser. No.61/802,034, filed Mar. 15, 2013, which is incorporated herein byreference in its entirety for all purposes.

STATEMENT OF GOVERNMENTAL SUPPORT

This invention was made with Government support under NS062009, awardedby the National Institutes of Health. The Government has certain rightsin the invention.

FIELD

This application relates to the field of neurological treatment andrehabilitation for injury and disease including traumatic spinal cordinjury, non-traumatic spinal cord injury, stroke, movement disorders,brain injury, ALS, Neurodegenerative Disorder, Dementia, Parkinson'sdisease, and other diseases or injuries that result in paralysis and/ornervous system disorder. Devices, pharmacological agents, and methodsare provided to facilitate recovery of posture, locomotion, andvoluntary movements of the arms, trunk, and legs, and recovery ofautonomic, sexual, vasomotor, speech, swallowing, and respiration, in ahuman subject having spinal cord injury, brain injury, or any otherneurological disorder.

BACKGROUND

Serious spinal cord injuries (SCI) affect approximately 1.3 millionpeople in the United States, and roughly 12-15,000 new injuries occureach year. Of these injuries, approximately 50% are complete spinal cordinjuries in which there is essentially total loss of sensory motorfunction below the level of the spinal lesion.

Neuronal networks formed by the interneurons of the spinal cord that arelocated in the cervical and lumbar enlargements, such as the spinalnetworks (SNs), can play an important role in the control of posture,locomotion and movements of the upper limbs, breathing and speech. Mostresearchers believe that all mammals, including humans, have SNs in thelumbosacral cord. Normally, the activity of SNs is regulatedsupraspinally and by peripheral sensory input. In the case of disordersof the connections between the brain and spinal cord, e.g., as a resultof traumatic spinal cord lesions, motor tasks can be enabled by epiduralelectrical stimulation of the lumbosacral and cervical segments as wellas the brainstem.

SUMMARY

We have demonstrated that enablement of motor function can be obtainedas well with the use of non-invasive external spinal cord electricalstimulation.

Various embodiments described herein are for use with a mammal including(e.g., a human or a non-human mammal) who has a spinal cord with atleast one selected dysfunctional spinal circuit or other neurologicallyderived source of control of movement or function in a portion of thesubject's body. Transcutaneous electrical spinal cord stimulation(tESCS) can be applied in the regions of the C4-C5, T11-T12 and/or L1-L2vertebrae with a frequency of 5-40 Hz. Such stimulation can elicitinvoluntary step-like movements in healthy subjects with their legssuspended in a gravity-neutral position. By way of non-limitingexamples, application of transcutaneous electrical spinal cordstimulation (tESCS) at multiple sites on the subject's spinal cord isbelieved to activate spinal locomotor networks (SNs), in part via thedorsal roots and the gray matter of the spinal cord. When activated, theSNs may, inter alia (a) enable voluntary movement of muscles involved inat least one of standing, stepping, reaching, grasping, voluntarilychanging positions of one or both legs, breathing, speech control,swallowing, voiding the patient's bladder, voiding the patient's bowel,postural activity, and locomotor activity; (b) enable or improveautonomic control of at least one of cardiovascular function, bodytemperature, and metabolic processes; and/or (c) help facilitaterecovery of at least one of an autonomic function, sexual function, orvasomotor function. According to some embodiments, the presentdisclosure provides that the spinal circuitry is neuromodulated to aphysiological state that facilitates or enables the recovery or improvedcontrol of movement and function following some neuromotor dysfunction.

The paralysis may be a motor complete paralysis or a motor incompleteparalysis. The paralysis may have been caused by a spinal cord injuryclassified as motor complete or motor incomplete. The paralysis may havebeen caused by an ischemic or traumatic brain injury. The paralysis mayhave been caused by an ischemic brain injury that resulted from a strokeor acute trauma. By way of another example, the paralysis may have beencaused by a neurodegenerative condition affecting the brain and/orspinal cord. The neurodegenerative brain injury may be associated withat least one of Parkinson's disease, Huntington's disease, Alzheimer's,Frontotemporal Dementia, dystonia, ischemic stroke, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), and other conditionssuch as cerebral palsy and Multiple Sclerosis.

By way of non-limiting example, a method includes applying electricalstimulation to a portion of a spinal cord or brainstem of the subject.The electrical stimulation may be applied by (or through) a surfaceelectrode(s) that is applied to the skin surface of the subject. Such anelectrode may be positioned at, at least one of a thoracic region, acervical region, a thoraco-lumbar region, a lumbosacral region of thespinal cord, the brainstem and/or a combination thereof. In certainembodiments the electrical stimulation is delivered at 5-40 Hz at 20-100mA. While not a requirement, the electrical stimulation may not directlyactivate muscle cells in the portion of the patient's body having theparalysis. The electrical stimulation may include at least one of tonicstimulation and intermittent stimulation. The electrical stimulation mayinclude simultaneous or sequential stimulation of different regions ofthe spinal cord.

If the paralysis was caused by a spinal cord injury at a first locationalong the spinal cord, the electrical stimulation may be applied by anelectrode that is on the spinal cord of the patient at a second locationbelow the first location along the spinal cord relative to the patient'sbrain.

Optionally, the method may include administering one or moreneuropharmaceutical agents to the patient. The neuropharmaceuticalagents may include at least one of a serotonergic drug, a dopaminergicdrug, a noradrenergic drug, a GABAergic drug, and glycinergic drugs. Byway of non-limiting examples, the neuropharmaceutical agents may includeat least one of 8-OHDPAT, Way 100.635, Quipazine, Ketanserin, SR 57227A,Ondanesetron, SB 269970, Buspirone, Methoxamine, Prazosin, Clonidine,Yohimbine, SKF-81297, SCH-23390, Quinpirole, and Eticlopride.

The electrical stimulation is defined by a set of parameter values, andactivation of the selected spinal circuit may generate a quantifiableresult. Optionally, the method may be repeated using electricalstimulation having different sets of parameter values to obtainquantifiable results generated by each repetition of the method. Then, amachine learning method may be executed by at least one computingdevice. The machine learning method builds a model of a relationshipbetween the electrical stimulation applied to the spinal cord and thequantifiable results generated by activation of the at least one spinalcircuit. A new set of parameters may be selected based on the model. Byway of a non-limiting example, the machine learning method may implementa Gaussian Process Optimization.

Another illustrative embodiment is a method of enabling one or morefunctions selected from a group consisting of postural and/or locomotoractivity, voluntary movement of leg position when not bearing weight,improved breathing and ventilation, speech control, swallowing,voluntary voiding of the bladder and/or bowel, return of sexualfunction, autonomic control of cardiovascular function, body temperaturecontrol, and normalized metabolic processes, in a human subject having aneurologically derived paralysis. The method includes stimulating thespinal cord of the subject using a surface electrode while subjectingthe subject to physical training that exposes the subject to relevantpostural proprioceptive signals, locomotor proprioceptive signals, andsupraspinal signals. At least one of the stimulation and physicaltraining modulates in real time provoke or incite theelectrophysiological properties of spinal circuits in the subject so thespinal circuits are activated by at least one of supraspinal informationand proprioceptive information derived from the region of the subjectwhere the selected one or more functions are facilitated.

The region where the selected one or more functions are facilitated mayinclude one or more regions of the spinal cord that control (a) lowerlimbs; (b) upper limbs and brainstem for controlling speech; (c) thesubject's bladder; (d) the subject's bowel and/or other end organ. Thephysical training may include, but need not be limited to, standing,stepping, sitting down, laying down, reaching, grasping, stabilizingsitting posture, and/or stabilizing standing posture. It is alsocontemplated that in certain embodiments, the physical training caninclude, but need not be limited to swallowing, chewing, grimacing,shoulder shrugging, and the like.

The surface electrode may include single electrode(s) or one or morearrays of one or more electrodes stimulated in a monopolar biphasicconfiguration, a monopolar monophasic configuration, or a bipolarbiphasic or monophasic configuration. Such a surface electrode may beplaced over at least one of all or a portion of a lumbosacral portion ofthe spinal cord, all or a portion of a thoracic portion of the spinalcord, all or a portion of a cervical portion of the spinal cord, thebrainstem or a combination thereof.

The stimulation may include tonic stimulation and/or intermittentstimulation. The stimulation may include simultaneous or sequentialstimulation, or combinations thereof, of different spinal cord regions.Optionally, the stimulation pattern may be under control of the subject.

The physical training may include inducing a load bearing positionalchange in the region of the subject where locomotor activity is to befacilitated. The load bearing positional change in the subject mayinclude standing, stepping, reaching, and/or grasping. The physicaltraining may include robotically guided training.

The method may also include administering one or moreneuropharmaceuticals. The neuropharmaceuticals may include at least oneof a serotonergic drug, a dopaminergic drug, a noradrenergic drug, aGABAergic drug, and a glycinergic drug.

Another illustrative embodiment is a method that includes placing anelectrode on the patient's spinal cord, positioning the patient in atraining device configured to assist with physical training that isconfigured to induce neurological signals in the portion of thepatient's body having the paralysis, and applying electrical stimulationto a portion of a spinal cord of the patient, such as a biphasic signalof 30-40 Hz at 85-100 mA.

Another illustrative embodiment is a system that includes a trainingdevice configured to assist with physically training of the patient, asurface electrode array configured to be applied on the patient's spinalcord, and a stimulation generator connected to the electrode. Whenundertaken, the physical training induces neurological signals in theportion of the patient's body having the paralysis. The stimulationgenerator is configured to apply electrical stimulation to theelectrode. Electrophysiological properties of at least one spinalcircuit in the patient's spinal cord is modulated by the electricalstimulation and at least one of (1) a first portion of the inducedneurological signals and (2) supraspinal signals such that the at leastone spinal circuit is at least partially activatable by at least one of(a) the supraspinal signals and (b) a second portion of the inducedneurological signals.

DEFINITIONS

The term “motor complete” when used with respect to a spinal cord injuryindicates that there is no motor function below the lesion, (e.g., nomovement can be voluntarily induced in muscles innervated by spinalsegments below the spinal lesion.

As used herein “electrical stimulation” or “stimulation” meansapplication of an electrical signal that may be either excitatory orinhibitory to a muscle or neuron. It will be understood that anelectrical signal may be applied to one or more electrodes with one ormore return electrodes.

The term “monopolar stimulation” refers to stimulation between a localelectrode and a common distant return electrode.

As used herein “epidural” means situated upon the dura or in very closeproximity to the dura. The term “epidural stimulation” refers toelectrical epidural stimulation. In certain embodiments epiduralstimulation is referred to as “electrical enabling motor control”(eEmc).

The term “transcutaneous stimulation” or “transcutaneous electricalstimulation” or “cutaneous electrical stimulation” refers to electricalstimulation applied to the skin, and, as typically used herein refers toelectrical stimulation applied to the skin in order to effectstimulation of the spinal cord or a region thereof. The term“transcutaneous electrical spinal cord stimulation” may also be referredto as “tSCS”.

The term “autonomic function” refers to functions controlled by theperipheral nervous system that are controlled largely below the level ofconsciousness, and typically involve visceral functions. Illustrativeautonomic functions include, but are not limited to control of bowel,bladder, and body temperature.

The term “sexual function” refers to the ability to sustain a penileerection, have an orgasm (male or female), generate viable sperm, and/orundergo an observable physiological change associated with sexualarousal.

The term “co-administering”, “concurrent administration”, “administeringin conjunction with” or “administering in combination” when used, forexample with respect to transcutaneous electrical stimulation, epiduralelectrical stimulation, and pharmaceutical administration, refers toadministration of the transcutaneous electrical stimulation and/orepidural electrical stimulation and/or pharmaceutical such that variousmodalities can simultaneously achieve a physiological effect on thesubject. The administered modalities need not be administered together,either temporally or at the same site. In some embodiments, the various“treatment” modalities are administered at different times. In someembodiments, administration of one can precede administration of theother (e.g., drug before electrical stimulation or vice versa).Simultaneous physiological effect need not necessarily require presenceof drug and the electrical stimulation at the same time or the presenceof both stimulation modalities at the same time. In some embodiments,all the modalities are administered essentially simultaneously.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an example embodiment illustrating peak EMG amplitudes in thevastus lateralis in response to epidural stimulation at L2 and/or S1spinal segments using nine combinations.

FIG. 2, panels A-C, provide an illustrative, but non-limiting, exampleof EMG and kinematic features of locomotor patterns induced by painlesstranscutaneous electrical spinal cord stimulation at the C5, T11, and L2vertebral levels in non-injured human subjects. Panels A, B: Angularmovements of the right (R) knee and left (L) knee joints andrepresentative EMG activity in the biceps femoris (BF) and medialgastrocnemius (MG) muscles of the right (R) and left (L) legs duringinvoluntary locomotor-like activity induced by transcutaneous spinalcord stimulation applied at the T11 vertebra alone (panel A) and at theC5+T11+L2 vertebrae simultaneously (panel B). Panel C: Stick diagramdecompositions (40 ms between sticks) of the movements of the right legduring one step cycle during transcutaneous spinal cord stimulation atT11, T11+L2, and C5+T11+L2 simultaneously. Arrows indicate the directionof movement.

FIG. 3 is one example embodiment illustrating the positioning of testsubjects

FIG. 4 is one example embodiment illustrating a graph depicting a 10 kHzbiphasic stimulation is delivered in 0.3 to 1 ms. These pulses aredelivered at 1-40 Hz.

FIGS. 5A and 5B are examples of an embodiment illustrating EMG andkinematic features of locomotor patterns induced by painlesstranscutaneous electrical spinal cord stimulation at the T11-T12vertebral level at 5 and 30 Hz of frequency in non-injured humansubjects. FIG. 5 shows angular movements of the right (R) knee and left(L) knee joints and representative EMG activity in the rectus femoris(RF), biceps femoris (BF) tibialis anterior (TA) and medialgastrocnemius (MG) muscles during involuntary locomotor-like activityinduced by transcutaneous spinal cord stimulation at the T11 vertebra at5 and 30 Hz. FIG. 5B shows stick diagram decompositions (40 ms betweensticks) of the movements of the R leg and trajectory of toe movementsduring one step cycle during PTES at T11-T12. Arrows in FIG. 5B indicatethe direction of movement.

FIG. 6 is an example of one embodiment illustrating EMG and kinematicfeatures of locomotor patterns induced by transcutaneous spinal cordstimulation at the C5, T11, and L2 vertebral levels. Angular movementsof the right (R) knee and left (L) knee joints and representative EMGactivity in the biceps femoris (BF) muscles of the R and left L legsduring involuntary locomotor-like activity induced by transcutaneousspinal cord stimulation at the C5+T11+L2 vertebrae simultaneously (left)and sequentially (right).

FIG. 7 is an example of one embodiment illustrating stick diagramdecompositions (40 ms between sticks) of the movements of the R legduring one step cycle during transcutaneous spinal cord stimulation atdifferent vertebral levels in two subjects are shown. Arrows indicatethe direction of movement.

DETAILED DESCRIPTION

Disclosed herein are methods for inducing locomotor activity in a mammalThese methods can comprise administering epidural or transcutaneouselectrical spinal cord stimulation (tSCS) to the mammal at a frequencyand intensity that induces the locomotor activity.

It is demonstrated herein in spinal rats (motor complete rats) andnon-injured human subjects that simultaneous spinal cord stimulation atmultiple sites has an interactive effect on the spinal neuralcircuitries responsible for generating locomotion. In particular, it wasdiscovered inter alia, that simultaneous multisite epidural stimulationwith specific parameters allows for a more precise control of thesepostural-locomotor interactions, resulting in robust, coordinatedplantar full weight-bearing stepping in complete spinal rats. The EMGstepping pattern during simultaneous multi-site epidural stimulation wassignificantly improved compared to certain bipolar stimulationconfigurations (e.g., between L2 and S1) or certain monopolarstimulation configurations (e.g., at L2 or S1). Without being bound to aparticular theory it is believed that one added benefit of second-site(e.g., S1 added to L2) stimulation with specific parameters may berelated to activation of postural neuronal circuitries and activation ofrostrally projecting propriospinal neurons from the more caudal segmentsthat contribute to the rhythm and pattern of output of the locomotorcircuitry.

It is also demonstrated herein using transcutaneous spinal cordstimulation in non-injured humans that the lumbosacral locomotorcircuitry can be accessed using a non-invasive pain free procedure. Inan illustrative, but non-limiting embodiment, it is shown thattranscutaneous spinal cord stimulation applied to stimulation at the L2spinal segment (T11-T12 vertebral level) is able to activate thislocomotor circuitry. It is believed the results demonstrated hereinprovide the first example of using multi-segmental non-invasiveelectrical spinal cord stimulation to facilitate involuntary,coordinated stepping movements.

Without being bound by a particular theory, it is believed that thesynergistic and interactive effects of multi-level stimulation in boththe animal and human studies indicates a multi-segmental convergence ofdescending and ascending, and most likely propriospinal, influences onthe spinal neuronal circuitries associated with locomotor and posturalactivity.

Accordingly, in some embodiments, the electrical spinal cord stimulationis applied at two spinal levels simultaneously. In other embodiments,the electrical spinal cord stimulation is applied at three spinal levelssimultaneously. In still over embodiments the electrical spinal cordstimulation is at four spinal levels simultaneously. The spinal levelscan be the cervical, thoracic, lumbar, sacral, or a combination thereof.In certain embodiments the spinal levels can be the cervical, thoracic,lumbar, or a combination thereof.

In certain embodiments, the stimulation can be to a brain stem and/orcervical level. In some embodiments, the brainstem/cervical level can bea region over at least one C0-C7 or C1-C7, over at least two of C0-C7 orC1-C7, over at least three of C0-C7 or C1-C7, over at least four ofC0-C7 or C1-C7, over at least five of C0-C7 or C1-C7, over at least sixof C0-C7 or C1-C7, over C1-C7, over C4-C5, over C3-C5, over C4-C6, overC3-C6, over C2-C5, over C3-C7, or over C3 to C7.

Additionally or alternatively, the stimulation can be to a thoraciclevel. In some embodiments, the thoracic level can be a region over atleast one of T1 to T12, at least two of T1 to T12, at least three of T1to T12, at least four of T1 to T12, at least five of T1 to T12, at leastsix of T1 to T12, at least seven of T1 to T12, at least 8 of T1 to T12,at least 9 of T1 to T12, at least 10 of T1 to T12, at least 11 of T1 toT12, T1 to T12, over T1 to T6, or over a region of T11-T12, T10-T12,T9-T12, T8-T12, T8-T11, T8 to T10, T8 to T9, T9-T12, T9-T11, T9-T10, orT11-T12.

Additionally or alternatively, the stimulation can be to a lumbar level.In some embodiments, the lumbar level can be a region over at least oneof L1-L5, over at least two of L1-L5, over at least three of L1-L5, overat least four of L1-L5, or L1-L5.

Additionally or alternatively, the stimulation can be to a sacral level.In some embodiments, the sacral level can be a region over at least oneS1-S5, over at least two of S1-S5, over late least three of S1-S5, overat least four of S1-S5, or over S1-S5. In certain embodiments, thestimulation is over a region including S1. In certain embodiments, thestimulation over a sacral level is over S1.

In some embodiments, the transcutaneous electrical spinal cordstimulation is applied paraspinally over regions that include, but neednot be limited to C4-C5, T11-T12, and/or L1-L2 vertebrae. In someembodiments, the transcutaneous electrical spinal cord stimulation isapplied paraspinally over regions that consist of regions over C4-C5,T11-T12, and/or L1-L2 vertebrae.

In various embodiments, the transcutaneous stimulation can be applied atan intensity ranging from about 30 to 200 mA, about 110 to 180 mA, about10 mA to about 150 mA, from about 20 mA to about 100 mA, or from about30 or 40 mA to about 70 mA or 80 mA.

In various embodiments the transcutaneous stimulation can be applied ata frequency ranging from about 1 Hz to about 100 Hz, from about 5 Hz toabout 80 Hz, or from about 5 Hz to about 30 Hz, or about 40 Hz, or about50 Hz.

As demonstrated herein, non-invasive transcutaneous electrical spinalcord stimulation (tSCS) can induce locomotor-like activity innon-injured humans. Continuous tSCS (e.g., at 5-40 Hz) appliedparaspinally over the T11-T12 vertebrae can induce involuntary steppingmovements in subjects with their legs in a gravity-independent position.These stepping movements can be enhanced when the spinal cord isstimulated at two to three spinal levels (C5, T12, and/or L2)simultaneously with frequency in the range of 5-40 Hz. Further,locomotion of spinal animals can be improved, in some embodimentssubstantially, when locomotor and postural spinal neuronal circuitriesare stimulated simultaneously.

In some embodiments, epidural spinal cord stimulation can be appliedindependently at the L2 and at the S1 spinal segments to facilitatelocomotion as demonstrated herein in complete spinal adult rats.Simultaneous epidural stimulation at L2 (40 Hz) and at S1 (10-20 Hz) canenable full weight-bearing plantar hindlimb stepping in spinal rats.Stimulation at L2 or S1 alone can induce rhythmic activity, but, in someembodiments, with minimal weight bearing. In non-injured human subjectswith the lower limbs placed in a gravity-neutral position,transcutaneous electrical stimulation (5 Hz) delivered simultaneously atthe C5, T11, and L2 vertebral levels facilitated involuntary steppingmovements that were significantly stronger than stimulation at T11alone. Accordingly, simultaneous spinal cord stimulation at multiplesites can have an interactive effect on the spinal circuitry responsiblefor generating locomotion.

By non-limiting example, transcutaneous electrical stimulation can beapplied to facilitate restoration of locomotion and other neurologicfunction in subjects suffering with spinal cord injury, as well as otherneurological injury and illness. Successful application can provide adevice for widespread use in rehabilitation of neurologic injury anddisease.

In embodiments, methods, devices, and optional pharmacological agentsare provided to facilitate movement in a mammalian subject (e.g., ahuman) having a spinal cord injury, brain injury, or other neurologicaldisease or injury. In some embodiments, the methods can involvestimulating the spinal cord of the subject using a surface electrodewhere the stimulation modulates the electrophysiological properties ofselected spinal circuits in the subject so they can be activated byproprioceptive derived information and/or input from supraspinal. Invarious embodiments, the stimulation may be accompanied by physicaltraining (e.g., movement) of the region where the sensory-motor circuitsof the spinal cord are located.

In some embodiments, the devices, optional pharmacological agents, andmethods described herein stimulate the spinal cord with, e.g.,electrodes that modulate the proprioceptive and supraspinal informationwhich controls the lower limbs during standing and/or stepping and/orthe upper limbs during reaching and/or grasping conditions. It is theproprioceptive and cutaneous sensory information that guides theactivation of the muscles in a coordinated manner and in a manner thataccommodates the external conditions, e.g., the amount of loading,speed, and direction of stepping or whether the load is equallydispersed on the two lower limbs, indicating a standing event,alternating loading indicating stepping, or sensing postural adjustmentssignifying the intent to reach and grasp.

Unlike approaches that involve specific stimulation of motor neurons todirectly induce a movement, the methods described herein enable thespinal circuitry to control the movements. More specifically, thedevices, optional pharmacological agents, and methods described hereincan exploit the spinal circuitry and its ability to interpretproprioceptive information and to respond to that proprioceptiveinformation in a functional way. In various embodiments, this is incontrast to other approaches where the actual movement isinduced/controlled by direct stimulation (e.g., of particular motorneurons).

In one embodiment, the subject is fitted with one or more surfaceelectrodes that afford selective stimulation and control capability toselect sites, mode(s), and intensity of stimulation via electrodesplaced superficially over, for example, the lumbosacral spinal cordand/or the thoracic spinal cord, and/or the cervical spinal cord tofacilitate movement of the arms and/or legs of individuals with aseverely debilitating neuromotor disorder.

In some embodiments, the subject is provided a generator control unitand is fitted with an electrode(s) and then tested to identify the mosteffective subject specific stimulation paradigms for facilitation ofmovement (e.g., stepping and standing and/or arm and/or hand movement).Using the herein described stimulation paradigms, the subject practicesstanding, stepping, reaching, grabbing, breathing, and/or speech therapyin an interactive rehabilitation program while being subject to spinalstimulation.

Depending on the site/type of injury and the locomotor activity it isdesired to facilitate, particular spinal stimulation protocols include,but are not limited to, specific stimulation sites along thelumbosacral, thoracic, cervical spinal cord or a combination thereof;specific combinations of stimulation sites along the lumbosacral,thoracic, cervical spinal cord and/or a combination thereof; specificstimulation amplitudes; specific stimulation polarities (e.g., monopolarand bipolar stimulation modalities); specific stimulation frequencies;and/or specific stimulation pulse widths.

In various embodiments, the system is designed so that the patient canuse and control in the home environment.

In various embodiments, the electrodes of electrode arrays are operablylinked to control circuitry that permits selection of electrode(s) toactivate/stimulate and/or that controls frequency, and/or pulse width,and/or amplitude of stimulation. In various embodiments, the electrodeselection, frequency, amplitude, and pulse width are independentlyselectable, e.g., at different times, different electrodes can beselected. At any time, different electrodes can provide differentstimulation frequencies and/or amplitudes. In various embodiments,different electrodes or all electrodes can be operated in a monopolarmode and/or a bipolar mode, using e.g., constant current or constantvoltage delivery of the stimulation.

In one illustrative but non-limiting system a control module is operablycoupled to a signal generation module and instructs the signalgeneration module regarding the signal to be generated. For example, atany given time or period of time, the control module may instruct thesignal generation module to generate an electrical signal having aspecified pulse width, frequency, intensity (current or voltage), etc.The control module may be preprogrammed prior to use or receiveinstructions from a programmer (or another source). Thus, in certainembodiments the pulse generator/controller is configurable by softwareand the control parameters may be programmed/entered locally, ordownloaded as appropriate/necessary from a remote site.

in certain embodiments the pulse generator/controller may include or beoperably coupled to memory to store instructions for controlling thestimulation signal(s) and may contain a processor for controlling whichinstructions to send for signal generation and the timing of theinstructions to be sent.

While in certain embodiments, two leads are utilized to providetranscutaneous stimulation, it will be understood that any number of oneor more leads may be employed. In addition, it will be understood thatany number of one or more electrodes per lead may be employed.Stimulation pulses are applied to electrodes (which typically arecathodes) with respect to a return electrode (which typically is ananode) to induce a desired area of excitation of electrically excitabletissue in one or more regions of the spine. A return electrode such as aground or other reference electrode can be located on same lead as astimulation electrode. However, it will be understood that a returnelectrode may be located at nearly any location, whether in proximity tothe stimulation electrode or at a more remote part of the body, such asat a metallic case of a pulse generator. It will be further understoodthat any number of one or more return electrodes may be employed. Forexample, there can be a respective return electrode for each cathodesuch that a distinct cathode/anode pair is formed for each cathode.

In various embodiments, the approach is not to electrically induce awalking pattern or standing pattern of activation, but toenable/facilitate it so that when the subject manipulates their bodyposition, the spinal cord can receive proprioceptive information fromthe legs (or arms) that can be readily recognized by the spinalcircuitry. Then, the spinal cord knows whether to step or to stand or todo nothing. In other words, this enables the subject to begin steppingor to stand or to reach and grasp when they choose after the stimulationpattern has been initiated.

Moreover, the methods and devices described herein are effective in aspinal cord injured subject that is clinically classified as motorcomplete; that is, there is no motor function below the lesion; howeverthe approach is not limited and may be used in subjects classified asmotor-incomplete. In various embodiments, the specific combination ofelectrode(s) activated/stimulated and/or the desired stimulation of anyone or more electrodes and/or the stimulation amplitude (strength) canbe varied in real time, e.g., by the subject. Closed loop control can beembedded in the process by engaging the spinal circuitry as a source offeedback and feedforward processing of proprioceptive input and byvoluntarily imposing fine tuning modulation in stimulation parametersbased on visual, and/or kinetic, and/or kinematic input from selectedbody segments.

In various embodiments, the devices, optional pharmacological agents,and methods are designed so that a subject with no voluntary movementcapacity can execute effective standing and/or stepping and/or reachingand/or grasping. In addition, the approach described herein can play animportant role in facilitating recovery of individuals with severealthough not complete injuries.

The approach described herein can provide some basic postural, locomotorand reaching and grasping patterns on their own. However, in someembodiments, the methods described herein can also serve as buildingblocks for future recovery strategies. In other embodiments, combiningtranscutaneous stimulation of appropriate spinal circuits with physicalrehabilitation and pharmacological intervention can provide practicaltherapies for complete SCI human patients. The methods described hereincan be sufficient to enable weight bearing standing, stepping and/orreaching or grasping in SCI patients. Such capability can give SCIpatients with complete paralysis or other neuromotor dysfunctions theability to participate in exercise, which can be beneficial, if nothighly beneficial, for their physical and mental health.

In other embodiments, the methods described herein can enable movementwith the aid of assistive walkers. In some embodiments, simple standingand short duration walking can increase these patients' autonomy andquality of life. The stimulating technology described herein (e.g.,transcutaneous electrical spinal cord stimulation) can provide a directbrain-to-spinal cord interface that can enable more lengthy and finercontrol of movements.

While the methods and devices described herein are discussed withreference to complete spinal injury, it will be recognized that they canapply to subjects with partial spinal injury, subjects with braininjuries (e.g., ischemia, traumatic brain injury, stroke, and the like),and/or subjects with neurodegenerative diseases (e.g., Parkinson'sdisease, Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), cerebral palsy,dystonia, and the like).

In various embodiments, the methods combine the use of transcutaneousstimulating electrode(s) with physical training (e.g., rigorouslymonitored (robotic) physical training), optionally in combination withpharmacological techniques. The methods enable the spinal cord circuitryto utilize sensory input as well as newly established functionalconnections from the brain to circuits below the spinal lesion as asource of control signals. The herein described methods can enable andfacilitate the natural sensory input as well as supraspinal connectionsto the spinal cord in order to control movements, rather than induce thespinal cord to directly induce the movement. That is, the presentlydescribed methods can facilitate and enhance intrinsic neural controlmechanisms of the spinal cord that exist post-SCI, rather than replaceor ignore them.

Processing of Sensory Input by the Spinal Cord: Using Afferents as aSource of Control

In various embodiments the methods and devices described herein canexploit spinal control of locomotor activity. For example, the humanspinal cord can receive sensory input associated with a movement such asstepping, and this sensory information can be used to modulate the motoroutput to accommodate the appropriate speed of stepping and level ofload that is imposed on lower limbs. In some embodiments, the presentmethods can utilize the central-pattern-generation-like properties ofthe human spinal cord (e.g., the lumbosacral spinal cord). Thus, forexample, exploiting inter alia the central-pattern-generation-likeproperietes of the lumbosacral spinal cord, oscillations of the lowerlimbs can be induced simply by vibrating the vastus lateralis muscle ofthe lower limb, by transcutaneous stimulation, and by stretching thehip. The methods described herein exploit the fact that the human spinalcord, in complete or incomplete SCI subjects, can receive and interpretproprioceptive and somatosensory information that can be used to controlthe patterns of neuromuscular activity among the motor pools necessaryto generate particular movements, e.g., standing, stepping, reaching,grasping, and the like.

Moreover, in certain embodiments, the methods described herein exploitthe fact that stimulation (e.g., transcutaneous stimulation) of multiplelevels can improve the ability of the spinal cord in complete orincomplete SCI subjects to receive and interpret proprioceptive andsomatosensory information that can be used to control the patterns ofneuromuscular activity among the motor pools necessary to generateparticular movements

In various embodiments, The methods described herein can facilitate andadapt the operation of the existing spinal circuitry that generates, forexample, cyclic step-like movements via a combined approach oftranscutaneous stimulation, physical training, and, optionally,pharmacology.

Facilitating Stepping and Standing in Humans Following a ClinicallyComplete Lesion

In various embodiments, the methods described herein can comprisestimulation of one or more regions of the spinal cord in combinationwith locomotory activities. In other embodiments, spinal stimulation canbe combined with locomotor activity thereby providing modulation of theelectrophysiological properties of spinal circuits in the subject sothey are activated by proprioceptive information derived from the regionof the subject where locomotor activity is to be facilitated. Further,spinal stimulation in combination with pharmacological agents andlocomotor activity may result in the modulation of theelectrophysiological properties of spinal circuits in the subject sothey are activated by proprioceptive information derived from the regionof the subject where locomotor activity is to be facilitated.

In certain embodiments of the presently described methods, locomotoractivity of the region of interest can be assisted or accompanied by anyof a number of methods known, for example, to physical therapists. Byway of illustration, individuals after severe SCI can generate standingand stepping patterns when provided with body weight support on atreadmill and manual assistance. During both stand and step training ofhuman subjects with SCI, the subjects can be placed on a treadmill in anupright position and suspended in a harness at the maximum load at whichknee buckling and trunk collapse can be avoided. Trainers positioned,for example, behind the subject and at each leg assist as needed inmaintaining proper limb kinematics and kinetics appropriate for eachspecific task. During bilateral standing, both legs can be loadedsimultaneously and extension can be the predominant muscular activationpattern, although co-activation of flexors can also occur. Additionally,or alternatively, during stepping the legs can be loaded in analternating pattern and extensor and flexor activation patterns withineach limb also alternated as the legs moved from stance through swing.Afferent input related to loading and stepping rate can influence thesepatterns, and training has been shown to improve these patterns andfunction in clinically complete SCI subjects.

Transcutaneous Electrical Stimulation of the Spinal Cord

As indicated above, without being bound by a particular theory, it isbelieved that transcutaneous electrical stimulation, e.g., over onespinal level, over two spinal levels simultaneously, or over threespinal levels simultaneously, in combination with physical training canfacilitate recovery of stepping and standing in human subjects followinga complete SCI.

In some embodiments, the location of electrode(s) and the stimulationparameters may be important in defining the motor response. In otherembodiments, the use of surface electrode(s), as described herein,facilitates selection or alteration of particular stimulation sites aswell as the application of a wide variety of stimulation parameters.

Use of Neuromodulatory Agents

In certain embodiments, the transcutaneous and/or epidural stimulationmethods described herein are used in conjunction with variouspharmacological agents, particularly pharmacological agents that haveneuromodulatory activity (e.g., are monoamergic). In certainembodiments, the use of various serotonergic, and/or dopaminergic,and/or noradrenergic and/or GABAergic, and/or glycinergic drugs iscontemplated. These agents can be used in conjunction with thestimulation and/or physical therapy as described above. This combinedapproach can help to put the spinal cord (e.g., the cervical spinalcord) in an optimal physiological state for controlling a range of handmovements.

In certain embodiments, the drugs are administered systemically, whilein other embodiments, the drugs are administered locally, e.g., toparticular regions of the spinal cord. Drugs that modulate theexcitability of the spinal neuromotor networks include, but are notlimited to combinations of noradrenergic, serotonergic, GABAergic, andglycinergic receptor agonists and antagonists. Illustrativepharmacological agents include, but are not limited to. agonists andantagonists to one or more combinations of serotonergic: 5-HT1A, 5-HT2A,5-HT3, and 5HT7 receptors; to noradrenergic alphal and 2 receptors; andto dopaminergic D1 and D2 receptors (see, e.g., Table 1).

TABLE 1 Illustrative pharmacological agents. Typical Typical Dose RangeName Target Action Route (mg/Kg) (mg/kg) Serotonergic receptor systems8-OHDPAT 5-HT1A7 Agonist S.C. 0.05 0.045-0.3  Way 100.635 5-HT1AAntagonist I.P. 0.5 0.4-1.5 Quipazine 5-HT2A/C Agonist I.P. 0.20.18-0.6  Ketanserin 5-HT2A/C Antagonist I.P. 3 1.5-6.0 SR 57227A 5-HT3Agonist I.P. 1.5 1.3-1.7 Ondanesetron 5-HT3 Antagonist I.P. 3 1.4-7.0SB269970 5-HT7 Antagonist I.P. 7  2.0-10.0 Noradrenergic receptorsystems Methoxamine Alpha1 Agonist I.P. 2.5 1.5-4.5 Prazosin Alpha1Antagonist I.P. 3 1.8-3.0 Clonidine Alpha2 Agonist I.P. 0.5 0.2-1.5Yohimbine Alpha2 Antagonist I.P. 0.4 0.3-0.6 Dopaminergic receptorsystems SKF-81297 D1-like Agonist I.P. 0.2 0.15-0.6  SCH-23390 D1-likeAntagonist I.P. 0.15  0.1-0.75 Quinipirole D2-like Agonist I.P. 0.30.15-0.3  Eticlopride D2-like Antagonist I.P. 1.8 0.9-1.8

The foregoing methods are intended to be illustrative and non-limiting.Using the teachings provided herein, other methods involvingtranscutaneous electrical stimulation and/or epidural electricalstimulation and/or the use of neuromodulatory agents to improve motorcontrol and/or strength of a hand or paw will be available to one ofskill in the art.

In various aspects, the invention(s) contemplated herein may include,but need not be limited to, any one or more of the followingembodiments:

Embodiment 1: A method of inducing locomotor activity in a mammal, saidmethod including administering transcutaneous electrical spinal cordstimulation (tSCS) to said mammal at a frequency and intensity thatinduces said locomotor activity.

Embodiment 2: The method of embodiment 1, wherein said mammal is ahuman.

Embodiment 3: The method of embodiment 2, wherein said electrical spinalcord stimulation is applied at two spinal levels simultaneously.

Embodiment 4: The method of embodiment 3, wherein said two spinal levelsare selected from cervical thoracic, lumbar or combinations thereof.

Embodiment 5: The method of embodiment 4, wherein said two spinal levelsinclude cervical and thoracic.

Embodiment 6: The method of embodiment 4, wherein said two spinal levelsinclude cervical and lumbar.

Embodiment 7: The method of embodiment 4, wherein said two spinal levelsinclude thoracic and lumbar.

Embodiment 8: The method of embodiment 2, wherein said electrical spinalcord stimulation is applied at three spinal levels simultaneously.

Embodiment 9: The method according to any one of embodiments 3-8,wherein stimulation to a cervical level is to a region over at least oneC1-C7, over at least two of C1-C7, over late least three of C1-C7, overat least four of C1-C7, over at least five of C1-C7, over at least sixof C1-C7, or over C1-C7.

Embodiment 10: The method according to any one of embodiments 3-8,wherein stimulation to a cervical level is to a region over C4-C5, overC3-C5, over C4-C6, over C3-C6, over C2-C5, over C3-C7, or over C3 to C7.

Embodiment 11: The method according to any one of embodiments 3-10,wherein stimulation to a thoracic level is to a region over at least oneof T1 to T12, at least two of T1 to T12, at least three of T1 to T12, atleast four of T1 to T12, at least five of T1 to T12, at least six of T1to T12, at least seven of T1 to T12, at least 8 of T1 to T12, at least 9of T1 to T12, at least 10 of T1 to T12, at least 11 of T1 to T12, or T1to T12.

Embodiment 12: The method of embodiment 11, wherein stimulation to athoracic level is to a region over T1 to T6, over a region of T11-T12,T10-T12, T9-T12, T8-T12, T8-T11, T8 to T10, T8 to T9, T9-T12, T9-T11,T9-T10, or T11-T12.

Embodiment 13: The method according to any one of embodiments 3-10,wherein stimulation to a lumbar level is to a region over at least oneof L1-L5, over at least two of L1-L5, over at least three of L1-L5, overat least four of L1-L5, or L1-L5.

Embodiment 14: The method of embodiment 2-3, wherein said transcutaneouselectrical spinal cord stimulation is applied paraspinally over C4-C5,T11-T12, or L1-L2 vertebrae.

Embodiment 15: The method according to any one of embodiments 2-3, and8, wherein said transcutaneous electrical spinal cord stimulation isapplied paraspinally over regions including one or more of C4-C5,T11-T12, or L1-L2 vertebrae.

Embodiment 16: The method of embodiment 15, wherein said transcutaneouselectrical spinal cord stimulation is applied paraspinally over regionsincluding two or more of C4-C5, T11-T12, or L1-L2 vertebrae.

Embodiment 17: The method according to any one of embodiments 2-3, and8, wherein said transcutaneous electrical spinal cord stimulation isapplied paraspinally over one or more of C4-C5, T11-T12, or L1-L2vertebrae.

Embodiment 18: The method of embodiment 17, wherein said transcutaneouselectrical spinal cord stimulation is applied paraspinally over two ormore of C4-C5, T11-T12, or L1-L2 vertebrae.

Embodiment 19: The method of embodiment 17, wherein said transcutaneouselectrical spinal cord stimulation is applied paraspinally over C4-C5,T11-T12, and L1-L2 vertebrae.

Embodiment 20: The method according to any one of embodiments 1-21,wherein said transcutaneous electrical stimulation is painlesstranscutaneous electrical stimulation (PTES).

Embodiment 21: The method according to any one of embodiments 1-20,wherein said transcutaneous stimulation is applied at an intensityranging from about 30 to 200 mA, about 110 to 180 mA, about 10 mA toabout 150 mA, from about 20 mA to about 100 mA, from about 30 or 40 mAto about 70 mA or 80 mA.

Embodiment 22: The method according to any one of embodiments 1-21,wherein said transcutaneous stimulation is applied at a frequencyranging from about 1 Hz to about 100 Hz, from about 3 Hz to about 90 Hz,from about 5 Hz to about 80 Hz, from about 5 Hz to about 30 Hz, or about40 Hz, or about 50 Hz.

Embodiment 23: The method according to any one of embodiments 1-22,wherein said mammal has a spinal cord injury.

Embodiment 24: The method of embodiment 23, wherein said spinal cordinjury is clinically classified as motor complete.

Embodiment 25: The method of embodiment 23, wherein said spinal cordinjury is clinically classified as motor incomplete.

Embodiment 26: The method according to any one of embodiments 1-22,wherein said mammal has an ischemic brain injury.

Embodiment 27: The method of embodiment 26, wherein said ischemic braininjury is brain injury from stroke or acute trauma.

Embodiment 28: The method according to any one of embodiments 1-22,wherein said mammal has a neurodegenerative brain injury.

Embodiment 29: The method of embodiment 28, wherein saidneurodegenerative brain injury is brain injury associated with acondition selected from the group consisting of Parkinson's disease,Huntington's disease, Alzhiemers, ischemic, stroke, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), dystonia, and cerebralpalsy.

Embodiment 30: The method according to any one of embodiments 1-29,wherein said locomotor/motor activity includes standing, stepping,reaching, grasping, speech, swallowing, or breathing.

Embodiment 31: The method according to any one of embodiments 1-30,wherein said locomotor activity includes a walking motor pattern.

Embodiment 32: The method according to any one of embodiments 1-31,wherein said locomotor activity includes sitting down, laying down,sitting up, or standing up.

Embodiment 33: The method according to any one of embodiments 1-32,wherein the stimulation is under control of the subject.

Embodiment 34: The method according to any one of embodiments 1-33,wherein said method further includes physical training of said mammal

Embodiment 35: The method of embodiment 34, wherein said physicaltraining includes inducing a load bearing positional change in saidmammal

Embodiment 36: The method according to embodiment 34, wherein the loadbearing positional change in said subject includes standing.

Embodiment 37: The method according to embodiment 34, wherein the loadbearing positional change in said subject includes stepping.

Embodiment 38: The method according to any one of embodiments 34-37,wherein said physical training includes robotically guided training.

Embodiment 39: The method according to any one of embodiments 1-38,wherein said method further includes administration of one or moreneuropharmaceuticals.

Embodiment 40: The method of embodiment 39, wherein saidneuropharmaceutical includes one or more agents selected from the groupconsisting of a serotonergic drug, a dopaminergic drug, and anoradrenergic drug.

Embodiment 41: The method of embodiment 39, wherein saidneuropharmaceutical includes a serotonergic drug.

Embodiment 42: The method of embodiment 41, wherein saidneuropharmaceutical includes the serotonergic drug 8-OHDPAT.

Embodiment 43: The method according to any one of embodiments 39-42,wherein said neuropharmaceutical includes the serotonergic drug Way100.635.

Embodiment 44: The method according to any one of embodiments 39-43,wherein said neuropharmaceutical includes the serotonergic drugQuipazine

Embodiment 45: The method according to any one of embodiments 39-44,wherein said neuropharmaceutical includes the serotonergic drugKetanserin, SR 57227A.

Embodiment 46: The method according to any one of embodiments 39-45,wherein said neuropharmaceutical includes the serotonergic drugOndanesetron

Embodiment 47: The method according to any one of embodiments 39-46,wherein said neuropharmaceutical includes the serotonergic drugSB269970.

Embodiment 48: The method according to any one of embodiments 39-47,wherein said neuropharmaceutical includes a dopaminergic drug.

Embodiment 49: The method according to any one of embodiments 39-48,wherein said neuropharmaceutical includes the dopaminergic drugSKF-81297.

Embodiment 50: The method according to any one of embodiments 39-49,wherein said neuropharmaceutical includes the dopaminergic drugSCH-23390.

Embodiment 51: The method according to any one of embodiments 39-50,wherein said neuropharmaceutical includes the dopaminergic drugQuinipirole.

Embodiment 52: The method according to any one of embodiments 39-51,wherein said neuropharmaceutical includes the dopaminergic drugEticlopride.

Embodiment 53: The method according to any one of embodiments 39-52,wherein said neuropharmaceutical includes a noradrenergic drug.

Embodiment 54: The method according to any one of embodiments 39-53,wherein said neuropharmaceutical includes the noradrenergic drugMethoxamine.

Embodiment 55: The method according to any one of embodiments 39-54,wherein said neuropharmaceutical includes the noradrenergic drugPrazosin.

Embodiment 56: The method according to any one of embodiments 39-55,wherein said neuropharmaceutical includes the noradrenergic drugClonidine.

Embodiment 57: The method according to any one of embodiments 39-56,wherein said neuropharmaceutical includes the noradrenergic drugYohimbine.

Embodiment 58: An electrical stimulator said stimulator configured toinduce locomotor or motor activity in a mammal according to anyone ofembodiments 1-54.

Embodiment 59: An electrical stimulator according to embodiment 58 incombination with the pharmaceutical as recited in any one of embodiments39-57 for use in inducing or restoring locomotor function in a mammal

Embodiment 60: The electrical stimulator of embodiment 59, wherein saidmammal has a spinal cord injury.

Embodiment 61: The electrical stimulator of embodiment 60, wherein saidspinal cord injury is clinically classified as motor complete.

Embodiment 62: The electrical stimulator of embodiment 60, wherein saidspinal cord injury is clinically classified as motor incomplete.

Embodiment 63: The electrical stimulator of embodiment 60, wherein saidmammal has an ischemic brain injury.

Embodiment 64: The electrical stimulator of embodiment 63, wherein saidischemic brain injury is brain injury from stroke or acute trauma.

Embodiment 65: The electrical stimulator of embodiment 60, wherein saidmammal has a neurodegenerative brain injury.

Embodiment 66: The electrical stimulator of embodiment 65, wherein saidneurodegenerative brain injury is brain injury associated with acondition selected from the group consisting of Parkinson's disease,Huntington's disease, Alzhiemers, ischemic, stroke, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), dystonia, and cerebralpalsy.

Illustrative, but non-limiting embodiments of the contemplated aredescribed herein. Variations on these embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. It is contemplated that skilled artisans can employ suchvariations as appropriate, and the application can be practicedotherwise than specifically described herein. Accordingly, manyembodiments of this application include all modifications andequivalents of the subject matter recited in the claims appended heretoas permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof isencompassed by the application unless otherwise indicated herein orotherwise clearly contradicted by context

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1

Six non-injured individuals were tested while lying on their right sidewith their legs supported in a gravity-independent position. tSCS wasdelivered using a 2.5 cm round electrode placed midline on the skinbetween the spinous processes of C4-C5, T11-T12, and/or L1-L2 as acathode and two 5.0×10.2 cm² rectangular plates made of conductiveplastic placed symmetrically on the skin over the iliac crests asanodes. Bipolar rectangular stimuli (1-msec duration) with a carrierfrequency of 10 kHz and at intensities ranging from 30 to 200 mA wereused. The stimulation was at 5 Hz and the exposure ranged from 10 to 30sec. The threshold intensity of tSCS applied at T12 that inducedinvoluntary stepping movements ranged from 110 to 180 mA. The sameintensity was used during stimulation of C5 and/or L2. The strongestfacilitation of stepping movements occurred when tSCS was applied at allthree levels simultaneously. The multi-segmental stimulation of thecervical, thoracic, and lumbar spinal cord initiated stepping movementsthat had a short latency of initiation (˜1 sec) and reached maximalamplitude within seconds. These data suggest that the synergistic andinteractive effects of multi-site stimulation reflect themulti-segmental convergence of descending and ascending, and most likelypropriospinal, influences on the spinal neuronal circuitry associatedwith locomotor activity. These data demonstrate the potential of anon-invasive means of stimulating the spinal cord, providing a new toolfor modulating spinal locomotor circuitries and facilitating locomotionafter a spinal cord injury.

Example Experimental Methods

Animal study:

Twelve adult female Sprague-Dawley rats (200-250 g body weight)underwent EMG and epidural stimulating electrode implantations andspinal cord transection surgeries. All experimental procedures wereapproved by the University of California Los Angeles Chancellor's AnimalResearch Committee and complied with the guidelines of the NationalInstitutes of Health Guide for the Care and Use of Laboratory Animals.

Bipolar intramuscular EMG electrodes were implanted in the vastuslateralis (VL), semitendinosus (St), medial gastrocnemius (MG), andtibialis anterior (TA) muscles. Epidural electrodes were implanted atthe L2 and S1 spinal segments. Spinal cord transection at T7-T8 wasperformed 14 days after the implantation of the EMG electrodes.Post-surgery, the bladders of all animals were expressed manually threetimes daily for the first two weeks and two times thereafter throughoutthe study. All of these procedures are performed routinely in our lab(Gerasimenko et al. (2007) J. Neurophysiol. 98: 2525-2536). The ratswere trained 5 days/week, 20 min/session for 3 weeks (15 trainingsessions) starting 7 days after the spinal cord transection surgery. Thetreadmill belt speed was increased progressively from 6 to 13.5 cm/s.

All rats were tested in the presence of epidural stimulation at spinalsegments L2 or S1 (monopolar stimulation) or at L2 and S1 simultaneouslyat intensities of 2.5 to 3.5 V. A stimulation frequency of 40 Hz with200 μs duration rectangular pulses was used during monopolarstimulation. For simultaneous stimulation, the stimulation frequency atL2 was set to 40 Hz whereas the stimulation frequency at S1 varied (5,10, 20, or 40 Hz).

Human Study.

Six non-injured individuals participated in this study. The subjectswere tested while lying on their right side with the upper leg supporteddirectly in the area of the shank and the lower leg placed on a rotatingbrace attached to a horizontal board supported by vertical ropes securedto hooks in the ceiling as described previously (Gerasimenko et al.(2010) J. Neurosci. 30: 3700-3708). The subjects were instructed not tovoluntarily intervene with the movements induced by the stimulation.Painless transcutaneous electrical stimulation (PTES) was deliveredusing a 2.5 cm round electrode (Lead_Lok, Sandpoint, United States)placed midline on the skin between the spinous processes of C4-C5,T11-T12 and L1-L2 as a cathode and two 5.0×10.2 cm2 rectangular platesmade of conductive plastic (Ambu, Ballerup, Germany) placedsymmetrically on the skin over the iliac crests as anodes. Step-likemovements were evoked by bipolar rectangular stimuli with 0.5 msduration filled with a carrier frequency of 10 kHz and at an intensityranging from 30 to 200 mA. The stimulation frequency was 5 Hz and theduration of exposure ranged from 10 to 30 s. Bilateral EMG activity wasrecorded from the biceps femoris, and medial gastrocnemius musclesthroughout the entire testing period using bipolar surface electrodes.EMG signals were amplified by a ME 6000 16-channel telemetricelectroneuromyograph (MegaWin, Finland). Flexion—extension movements atthe knee joints were recorded.(training sessions) starting 7 days afterthe using goniometers. Reflective markers were placed bilaterally on thelateral epicondyle of the humerus, greater trochanter, lateralepicondyle of the femur, lateral malleolus, and hallux. Kinematicsmeasures of leg movements were recorded using the Qualisy video system(Sweden). A single step cycle during stable stepping is illustrated toshow the coordination between joint movements (FIG. 2, panel C).

Example 3 Effects of Combinations of Epidural Stimulation on HindlimbEMG Activity in Spinal Rats

Among all combinations of epidural stimulation parameters used to evokebipedal stepping in spinal rats, simultaneous stimulation at L2 (40 Hz)and S1 (5-15 Hz) produced the most coordinated and robust EMG steppingpattern in the hindlimb muscles. FIG. 1 shows the mean (14steps/condition) peak EMG amplitudes of the antigravity muscle, inresponse to different combinations of epidural stimulation in a spinalrat. The peak amplitudes of filtered raw EMG signals from the same ratwere 25-fold higher in all hindlimb muscles when tested duringsimultaneous epidural stimulation at L2 (40 Hz) and S1 (20 Hz) comparedto L2 monopolar stimulation.

Example 4 PTES-Induced Involuntary Locomotor-Like Activity in HumanSubjects

PTES was easily tolerated by subjects and did not cause pain even whenthe strength of current was increased to 200 mA. Lack of pain can beattributed to the use of biphasic stimuli with a carrier frequency of 10kHz that suppresses the sensitivity of pain receptors. The thresholdintensity of the stimulus that induced involuntary stepping movementsranged from 110 to 180 mA. PTES at a frequency of 5 Hz applied to T11alone caused step-like movements in five out of the six tested subjects(see FIG. 2, panel A). The involuntary stepping movements induced byPTES were reflected in the alternating EMG bursting activity insymmetric muscles of the left and right legs as well as the alternationof the EMG bursts in antagonist muscles of the hip and shank. Thesemovements were further facilitated with simultaneous stimulation ateither C5 or L2. The strongest facilitation of stepping movementsoccurred when PTES was applied at all three levels simultaneously (seeFIG. 2, panel B).

The multi-segmental stimulation of the cervical, thoracic, and lumbarspinal cord initiated stepping movements had a short latency ofinitiation (-1 sec) and reached maximal amplitude within sec (see FIG.2, panel B). Importantly, immediately after simultaneous PTES of thecervical, thoracic, and lumbar spinal cord, the right and left kneesmoved in opposite directions clearly reflecting a distinct alternatingstepping pattern (see FIG. 2, panel C). Although the kinematics (jointangles, trajectory characteristics) of the lower limb movements werequalitatively similar during PTES at T11, T11+L2, or C5+T11+L2,stimulation at the three spinal levels simultaneously producedflexion-extension movements with larger amplitudes than stimulation ateither one or two segments (see FIG. 2, panel C).

The obtained results from both spinal rats and human subjects suggestthat simultaneous spinal cord stimulation at multiple sites has aninteractive effect on the spinal neural circuitries responsible forgenerating locomotion. Thus, in some embodiments, simultaneous multisiteepidural stimulation with specific parameters can allow for a moreprecise control of these postural-locomotor interactions, resulting inrobust, coordinated plantar full weight-bearing stepping in completespinal rats. For example, the EMG stepping pattern during simultaneousmulti-site epidural stimulation was significantly improved compared tobipolar stimulation between L2 and S1 or monopolar stimulation at L2 orS1 (FIG. 1). An added benefit of second-site (S1 added to L2)stimulation with specific parameters may be related to activation ofpostural neuronal circuitries and activation of rostrally projectingpropriospinal neurons from the more caudal segments that contribute tothe rhythm and pattern of output of the locomotor circuitry.

In some embodiments, accessing the lumbosacral locomotor circuitry canbe accomplished using the present methods in a noninvasive, pain-freeprocedure. In other embodiments of the present methods, PTES applied tothe same level of the spinal cord is also able to activate locomotorcircuitry. In still other embodiments, the present methods can usemulti-segmental non-invasive electrical spinal cord stimulation tofacilitate involuntary, coordinated stepping movements.

Further, the present methods can provide synergistic and interactiveeffects of stimulation in both animals and humans. This synergistic andinteractive effect can result from a multi-segmental convergence ofdescending and ascending, for example, propriospinal, influences on thespinal neuronal circuitries associated with locomotor and posturalactivity.

Example 5

In other embodiments, stepping movements can be enhanced when the spinalcord is stimulated at two to three spinal levels (e.g., C5, T12, and/orL2) simultaneously.

The subjects were tested while lying on their right side with the upperleg supported directly in the area of the shank and the lower leg placedon a rotating brace attached to a horizontal board supported by verticalropes secured to hooks in the ceiling (FIG. 3). The subjects wereinstructed not to voluntarily intervene with the movements induced bythe stimulation. Painless transcutaneous electrical stimulation (PTES)was delivered using a 2.5 cm round electrode (Lead_Lok, Sandpoint,United States) placed midline on the skin between the spinous processesof C4-C5, T11-T12 and L1-L2 as a cathode and two 5.0×10.2 cm²rectangular plates made of conductive plastic (Ambu, Ballerup, Germany)placed symmetrically on the skin over the iliac crests as anodes.Step-like movements were evoked by bipolar rectangular stimuli with 0.5ms duration filled with a carrier frequency of 10 kHz and at anintensity ranging from 30 to 200 mA. The stimulation frequency was 5 Hzand the duration of exposure ranged from 10 to 30s.

TES was easily tolerated by subjects and did not cause pain even whenthe strength of current was increased to 200 mA. Lack of pain can beattributed to the use of biphasic stimuli with a carrier frequency of 10kHz that suppresses the sensitivity of pain receptors. The thresholdintensity of the stimulus that induced involuntary stepping movementsranged from 110 to 180 mA (FIG. 4).

MG and kinematics features of locomotor patterns induced by painlesstranscutaneous electrical stimulation at the T11-T12 vertebral level at5 and 30 Hz of frequency in non-injured human subjects are shown inFIGS. 5A and 5B. Angular movements of the right (R) knee and left (L)knee joints and representative EMG activity in the rectus femoris (RF),biceps femoris (BF) tibialis anterior (TA) and medial gastrocnemius (MG)muscles during involuntary locomotor-like activity induced by PTES atthe T11 vertebra. Stick diagram decompositions (40 ms between sticks) ofthe movements of the R leg and trajectory of toe movements during onestep cycle during PTES at T11-T12 are shown in FIG. 5B. Arrows in FIG.5B indicate the direction of movement.

EMG and kinematics features of locomotor patterns induced by PTES at theC5, T11, and L2 vertebral levels (FIG. 6). Angular movements of theright (R) knee and left (L) knee joints and representative EMG activityin the biceps femoris (BF) muscles of the R and left L legs duringinvoluntary locomotor-like activity induced by PTES at the C5+T11+L2vertebrae simultaneously (left) and sequentially (right).

FIG. 7 shows stick diagram decompositions (40 ms between sticks) of themovements of the R leg during one step cycle during PTES at differentvertebral levels in two subjects are shown. Arrows indicate thedirection of movement. Multi-segmental non-invasive electrical spinalcord stimulation was used to facilitate involuntary, coordinatedstepping movements. Simultaneous spinal cord stimulation at multiplesites can have an interactive effect on the spinal neural circuitriesresponsible for generating locomotion. The synergistic and interactiveeffects of multi-site spinal cord stimulation can be a multi-segmentalconvergence of descending and ascending, and most likely propriospinal,influences on the spinal circuitries associated with locomotor andpostural activity.

The various methods and techniques described above provide a number ofways to carry out the application. Of course, it is to be understoodthat not necessarily all objectives or advantages described can beachieved in accordance with any particular embodiment described herein.Thus, for example, those skilled in the art will recognize that themethods can be performed in a manner that achieves or optimizes oneadvantage or group of advantages as taught herein without necessarilyachieving other objectives or advantages as taught or suggested herein.A variety of alternatives are mentioned herein. It is to be understoodthat some preferred embodiments specifically include one, another, orseveral features, while others specifically exclude one, another, orseveral features, while still others mitigate a particular feature byinclusion of one, another, or several advantageous features.

Furthermore, the skilled artisan will recognize the applicability ofvarious features from different embodiments. Similarly, the variouselements, features and steps discussed above, as well as other knownequivalents for each such element, feature or step, can be employed invarious combinations by one of ordinary skill in this art to performmethods in accordance with the principles described herein. Among thevarious elements, features, and steps some will be specifically includedand others specifically excluded in diverse embodiments.

Although the application has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the embodiments of the application extend beyond thespecifically disclosed embodiments to other alternative embodimentsand/or uses and modifications and equivalents thereof.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A method of inducing locomotor activity in amammal, said method comprising administering transcutaneous electricalspinal cord stimulation (tSCS) to said mammal at a frequency andintensity that induces said locomotor activity.
 2. The method of claim1, wherein said mammal is a human.
 3. The method of claim 2, whereinsaid transcutaneous electrical spinal cord stimulation is appliedparaspinally over C4-C5, T11-T12 and/or L1-L2 vertebrae.
 4. The methodaccording to anyone of claims 1-3, wherein said transcutaneousstimulation is applied at an intensity ranging from about 30 to 200 mA,about 110 to 180 mA, about 10 mA to about 150 ma, more preferably fromabout 20 mA to about 100 mA, still more preferably from about 30 or 40mA to about 70 mA or 80 mA.
 5. The method according to anyone of claims1-4, wherein said transcutaneous stimulation is applied at a frequencyranging from about 3 Hz to about 100 Hz, more preferably from about 5 Hzto about 80 Hz, still more preferably from about 5 Hz to about 30 Hz, orabout 40 Hz, or about 50 Hz.
 6. The method according to anyone of claims1-5, wherein said mammal has a spinal cord injury.
 7. The method ofclaim 6, wherein said spinal cord injury is clinically classified asmotor complete.
 8. The method of claim 6, wherein said spinal cordinjury is clinically classified as motor incomplete.
 9. The methodaccording to anyone of claims 1-5, wherein said mammal has an ischemicbrain injury.
 10. The method of claim 9, wherein said ischemic braininjury is brain injury from stroke or acute trauma.
 11. The methodaccording to anyone of claims 1-5, wherein said mammal has aneurodegenerative brain injury.
 12. The method of claim 11, wherein saidneurodegenerative brain injury is brain injury associated with acondition selected from the group consisting of Parkinson's disease,Huntington's disease, Alzhiemers, ischemic, stroke, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), and cerebral palsy.13. The method according to anyone of claims 1-12, wherein saidlocomotor activity comprises standing, stepping, speech, swallowing orbreathing.
 14. The method according to anyone of claims 1-12, whereinsaid locomotor activity comprises a walking motor pattern.
 15. Themethod according to anyone of claims 1-12, wherein said locomotoractivity comprises sitting down or laying down.
 16. The method accordingto anyone of claims 1-15, wherein the stimulation is under control ofthe subject.
 17. The method according to anyone of claims 1-16, whereinsaid method further comprises physical training of said mammal.
 18. Themethod of claim 17, wherein said physical training comprises inducing aload bearing positional change in said mammal.
 19. The method accordingto claim 17, wherein the load bearing positional change in said subjectcomprises standing.
 20. The method according to claim 17, wherein theload bearing positional change in said subject comprises stepping. 21.The method according to anyone of claims 17-20, wherein said physicaltraining comprises robotically guided training.
 22. The method accordingto anyone of claims 1-21, wherein said method further comprisesadministration of one or more neuropharmaceuticals.
 23. The method ofclaim 22, wherein said neuropharmaceutical comprises one or more agentsselected from the group consisting of a serotonergic drug, adopaminergic drug, and a noradrenergic drug.
 24. An electricalstimulator said stimulator configured to induce locomotor activity in amammal according to anyone of claims 1-16.